Atrophic age-related macular degeneration (AMD) affects more than 9 million individuals in the United States. With the increased longevity of the US population, this number will increase to ˜17.8 million by 2050. The economic burden is estimated at ˜$25 billion in lost gross domestic product. In 2004, the direct medical cost of age related macular degeneration treatment was estimated to be $575 million, excluding nursing home costs, productivity losses, and home health care costs.
Diabetic retinopathy is another leading cause of new cases of legal blindness among adults aged 20 to 74 years in the United States. The estimated prevalence of diabetic retinopathy and vision-threatening diabetic retinopathy was 28.5% and 4.4% among US adults with diabetes, respectively. Diabetes-related blindness is a personal catastrophe to the individual and costs the United States approximately $500 million annually. The development of a sustained release delivery system would expand the list of therapies that could be utilized to treat several chronic intraocular diseases including age related macular degeneration and diabetic retinopathy.
Glaucoma is the second leading cause of blindness in the world, according to the World Health Organization. Approximately 120,000 are blind from glaucoma, accounting for 9% to 12% of all cases of blindness in the United States. In terms of Social Security benefits, lost income tax revenues, and health care expenditures, the cost to the U.S. government is estimated to be over $1.5 billion annually.
Leber congenital amaurosis (LCA) is a rare, hereditary disorder that leads to retinal dysfunction and visual impairment at an early age, often from birth. Of all the retinal degenerations, it has the earliest age of onset and can be the most severe. The birth prevalence of LCA is two to three per 100,000 births. LCA accounts for the cause of blindness in more than 20% of children attending schools for the blind.
The development of a sustained release delivery system would expand the list of therapies that could be utilized to treat several chronic intraocular diseases such as, age related macular degeneration, diabetic retinopathy, glaucoma, Leber congenital amaurosis, etc.
Efficacious drug delivery to chronic diseases and disorders can be limited by dosing frequency. For example, drug delivery to the posterior segment of the eye is inherently limited by barriers created by the structures of the eye (e.g., the thick scleral tunic, absorption of the drops by the conjunctival and nasal vasculature, tight junctions between retinal pigment epithelium cells). The most direct route for administration of therapeutic drugs to the tissues in the back of an eye is via intravitreal injections. However, this route is limited by frequent need for repeat dosages, which can cause complications, such as endophthalmitis and retinal detachment. It would be ideal to have an injectable biodegradable device made of non-toxic materials that offered many advantages, such as an increase in the half-life of the drug, no need for removal of an implant and circumvention of the first-order kinetics of drug delivery that are experienced following injection of the drug alone (i.e., rapid rise in drug concentration followed by a rapid decrease).
There are several modes by which drugs can be administered to the posterior segment of the eye including systemic circulation, eye drops, transcleral delivery or intraocular injections. Systemic circulation, eye drops, and transcleral delivery methods are limited by barriers created by the structures of the eye (e.g., the thick scleral tunic, absorption of the drops by the conjunctival and nasal vasculature, tight junctions between retinal pigment epithelium cells). Therefore, intravitreal injection is the safest and most effective route for administration of therapeutic drugs to the target tissues of the back of the eye, especially the retina. However, it is critical to limit the number of repeated injections to minimize the risk of infection or retinal detachment.
A nanoparticle drug delivery system has many technological advantages such as longer shelf life, ability to carry both hydrophilic and lipophilic substances, and high drug loading capacity. Nanoparticles can also be designed to allow sustained drug release from the particulate system in the treatment of chronic diseases in order to enable reduction of dosing frequency in certain drugs. Drug-loaded nanoparticles constitute a versatile drug delivery system and have the ability to overcome physiological barriers and guide the drug to specific cells or intracellular compartments either by passive or ligand-mediated targeting mechanisms.
For ophthalmic applications, biodegradable polymer, poly(ortho ester) have been used as bolus drug depots. Poly(ortho ester)s are hydrophobic polymers, degraded by surface erosion confined to the polymer-water interfaces following zero-order drug release kinetics when placed in a biological environment. The erosion rate of a poly(ortho ester) polymer is controlled by the incorporation of a latent acid such as lactic acid (LA), resulting in a 4th generation poly(ortho ester) polymer (poly(ortho ester) IV) (Schwach-Abdellaoui, K.; Heller, J.; Gurny, R. Hydrolysis and erosion studies of autocatalyzed poly(ortho esters) containing lactoyl-Lactyl acid dimers, Macromolecules 1999, 32, 301-307). While poly(ortho ester)s have been evaluated as a bolus drug delivery system and have minimal to no toxic effects (Einmahl, S.; Ponsart, S.; Bejjani, R. A.; D'Hermies, F.; Savoldelli, M; Heller, J.; Tabatabay, C.; Gurny, R.; Behar-Cohen, F. Ocular biocompatibility of a poly(orthoester) characterized by autocatalyzed degradation. Jthenal of Biomedical Materials Research, Part A, 2003, 67, 44-53), this polymer has not been used to generate nanoparticles for use as an intraocular delivery system.
To avoid frequent intravitreal injections, which can cause complications such as endophthalmitis and retinal detachment, a biodegradable, biocompatible, and long-term controlled release drug delivery system is highly desirable.